Combination analgesics, including acetaminophen with opioids, are used extensively for pain management in the elderly (and others). This is, in part, because these combinations can produce analgesia that is additive or synergistic, and the adverse effects produced by the combinations can be less than those produced by equianalgesic doses of either component alone. Even so, the acetaminophen in these combinations can cause hepatotoxicity after ingestion of large doses or from chronic use, particularly in the elderly or when liver function is compromised. The opioid dosages need to be escalated in response to the tolerance that is developed from chronic use, increasing the occurrence of adverse side effects in the elderly. We have been exploring a series of new and proprietary derivatives of acetaminophen, in which the lead compound (SCP-1) has good oral efficacy in both young and aged animals, and produces little, if any, hepatotoxicity. This Phase I SBIR project explores the feasibility that combinations of SCP-1 + codeine can have synergistic effects comparable to or better than acetaminophen + codeine combinations, but with reduced side effects, in models of acute and chronic pain management using young and old animals. It will also determine (in both young and old animals) the development of tolerance and dependence after chronic dosing, as well as hepatotoxicity after chronic and acute dosing. If the SCP-1 with codeine is shown to be more efficacious and/or less toxic than acetaminophen with codeine, further drug development will be proposed under a Phase II SBIR with eventual clinical trials in elderly patients who require management of acute or chronic pain.